Apoptosis is a characteristic form of cell death involving activation of one or more internally controlled pathways leading to autodigestion. Apoptosis can be induced by the binding and cross-linking of a cell surface receptor known as Fas. Human Fas (also known as APO-1 and CD95) is a cell surface protein consisting of 325 amino acids with a signal sequence at the NH.sub.2 -terminus and a membrane spanning region in the middle of the molecule. Fas appears to be constitutively expressed on cells of a varied, but limited, number of normal tissues, including skeletal muscle, liver, skin, heart, lung, kidney, reproductive tissues, neutrophils and macrophages. Malignant cells of hematologic or non-hematologic origin have also been demonstrated to express Fas (see, e.g., Leithauser et al., 1993, Laboratory Invest. 69:415).
Fas-mediated apoptosis (also known as Fas-mediated cytotoxicity) requires cross-linking of Fas with either agonistic anti-Fas antibody, with cell bound FasL (Fas-ligand), or with soluble FasL (see, e.g. Alderson et al., 1995, J. Exp. Med. 181: 71-77). FasL is a type II transmembrane protein of the tumor necrosis factor family. Depending on the tumor type, FasL cell surface expression is variable; e.g., detectable in some tumors and absent in others. For those tumors expressing FasL, it has been suggested that such expression provides a mechanism of immune privilege of the tumors; i.e. a means by which the tumor evades immune-induced tumor cell depletion (Walker et al., 1997 J. Immunol. 158:4521-4). For example, FasL+ hepatocellular carcinomas were shown to kill Fas+ T lymphocytic cells in coculture (Strand et al., 1996, Nat. Med. 2:1361-6); FasL+ human colonic adenocarcinoma cell lines induced apoptosis of Fas+ T lymphocytic cells in coculture (SW480, Shiraki et al., 1997, Proc. Natl. Acad. Sci. USA 94:6420-5; SW620, O'Connell et al., 1996, J. Exp. Med. 184:1075-82); FasL+ human lung carcinoma cell lines killed Fas+ T lymphocytic cells in coculture (Niehans et al., 1997, Cancer Res. 57:1361-6); and FasL+ melanoma cells induced apoptosis of Fas+ target cells in coculture (Hahne et al., 1996, Science 274:1363-6). These data suggest that FasL expression by tumor cells enhances tumorigenesis by killing Fas expressing immune effector cells (e.g., activated or tumor-reactive T cells) and surrounding Fas expressing tissue cells (e.g., hepatocytes; see Shiraki et al., 1997, supra). Further, cancer cells found to be FasL+ and Fas+ fail to undergo Fas-mediated apoptosis after treatment with agonistic anti-Fas antibody (O'Connell et al., 1996, supra) suggesting that tumor-expressed Fas did not transmit an apoptotic signal. Resistance to Fas-mediated apoptosis after anti-Fas antibody treatment has also been observed in nonhematopoietic tumors (Owen-Schaub et al., 1994, Cancer Res. 54:1580-1586), human hepatoma cells (Ni et al., 1994, Exp. Cell Res. 215:332-7), breast carcinoma (Keane et al., 1996, Cancer Res. 56:4791-8). Thus, that tumor cells (e.g., from breast, colon, testis, and liver) expressing Fas appear to have lost their sensitivity to anti-Fas mediated cytotoxicity, suggests that tumor cells escape the normal induction of apoptosis that occurs in these tissues (Micheau et al., 1997, J. Natl. Cancer Inst. 89:783-789).
A need still exists for a method to impair or inhibit metastasis and tumor cell growth, and with less systemic toxicity than the current standard treatments comprising chemotherapy and/or radiation therapy.